Electrical and synaptic integration of glioma into neural circuits

High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that n...

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Bibliographic Details
Published in:	Nature (London) 2019-09, Vol.573 (7775), p.539-545
Main Authors:	Venkatesh, Humsa S, Morishita, Wade, Geraghty, Anna C, Silverbush, Dana, Gillespie, Shawn M, Arzt, Marlene, Tam, Lydia T, Espenel, Cedric, Ponnuswami, Anitha, Ni, Lijun, Woo, Pamelyn J, Taylor, Kathryn R, Agarwal, Amit, Regev, Aviv, Brang, David, Vogel, Hannes, Hervey-Jumper, Shawn, Bergles, Dwight E, Suvà, Mario L, Malenka, Robert C, Monje, Michelle
Format:	Article
Language:	eng
Subjects:	Animals Bioinformatics Biopsy Brain Brain - cytology Brain - physiopathology Brain cancer Cell adhesion & migration Cell Membrane - pathology Cell Proliferation Cell survival Circuits Communication Cortex Depolarization Editing Electrical Synapses - pathology Electrochemistry Electrophysiological Phenomena Excitability Gap Junctions - pathology Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Genetics Glioma Glioma - physiopathology Growth factors Heterografts Humans Information processing Integration Membranes Mice Mice, Inbred NOD Microscopy Nervous system Neural networks Neurons Neurons - pathology Optics Optogenetics Positive feedback Potassium Potassium - metabolism Potassium currents Principal components analysis Synapses Synaptic Transmission Tumor Cells, Cultured Tumors Xenografts Xenotransplantation α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
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Summary:	High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.
ISSN:	0028-0836 1476-4687